The interstitial connective tissue in the peripheral nerve that separates the individual nerve fibers of a vertebrate is referred to as the endoneurium, and can be visualized as an insulative medium in which conductive wires are embedded. Blood vessels in the endoneurium of peripheral nerves are comparable to those of the central nervous system and are lined by a continuous endothelium, made up of capillary endothelial cells, with intercellular tight junctions of high electrical resistance (100 ohm/cm.sup.2). Together with the perineurium, a connective tissue sheath immediately surrounding the fascicles of nerve fibers, the vessels form a blood-nerve barrier (BNB) to regulate the microenvironment of the endoneurium of the nerve. The blood-cerebrospinal fluid barrier and the blood brain barrier (collectively the "BBB") are also associated with the tight junctions which adjoin adjacent capillary endothelial cells within the brain and spinal cord, to regulate this microenvironment as well.
The BNB and BBB are effective barriers to both endogenous and exogenously-administered blood components, including peptides, proteins and other large macromolecules, as well as to ions and water-soluble non-electrolytes. This protects the brain or endoneurial microenvironment from rapid changes in the composition of the blood or of the extraneural spaces. Also, alterations in BBB or BNB integrity are implicated in a number of brain and peripheral nerve disorders, such as those caused by diabetes mellitus, toxins, infection and autoimmune disorders.
However, the ability of the BNB and BBB to protect the nervous system from exogenous substances has impeded the development of both diagnostic assays and therapies for a wide variety of neural pathologies and disorders. Thus, a continuing need exists for methods to increase the permeability of the BNB or the BBB to bioactive substances, particularly to bioactive peptides and proteins.